1. Field of the Invention
This invention is directed to a di-steroidal prodrug of ethinyl estradiol and pharmaceutically acceptable salts thereof. The invention also includes pharmaceutical dosage units of the di-steroidal prodrug and a method of forming the di-steroidal prodrug of ethinyl estradiol.
2. Related Background Art
Unbound 17β-estradiol is the most active, naturally occurring human estrogen. However, due to poor absorption and extensive first-pass metabolism in the gastrointestinal tract and liver following oral absorption, it is not generally orally active. Methods of increasing activity have included the use of micronized drugs to improve absorption and the use of prodrugs such as estradiol-17-valerate and equine estrogens which are a combination of sulphate and glucuronide derivatives (Martindale 32ed, 1999, Pharmaceutical Press).
Another method of increasing activity is to alter the structure of the 17β-estradiol. Ethinyl estradiol is an example of this. The ethinyl group on the 17 position greatly reduces liver first-pass metabolism compared to 17β-estradiol, enabling the compound to be more active than the natural estrogen, 17β-estradiol (Martindale 32ed, 1999, Pharmaceutical Press).
Ethinyl estradiol is the most common estrogen used in contraceptive preparations. Given its increased potency over 17β-estradiol it is used in comparatively lower doses (i.e., orally 15 to 50 μg per day) (Martindale 32ed, 1999, Pharmaceutical Press). It is also more potent by other routes of administration, i.e., vaginally where it can be employed at a daily dose of 15 μg (see U.S. Pat. No. 5,989,581). It has also been used in Hormone Replacement Therapy although to a lesser extent than 17β-estradiol.
U.S. Pat. No. 3,916,002 to Taubert et al. describes a number of oligomeric steroid esters having the formula: R—O—CO—(CH2)n—CO—O—R, wherein n is between 2 and 8, and each R is a monovalent steroid radical. The steroid radical is derived from steroids having a hydroxyl substituent at one of the carbon atoms numbered 3, 16 or 17. They can be produced by esterification of the two carboxyl radicals of a dicarboxylic acid with a steroid alcohol having a hydroxyl radical substituent at carbon atoms numbered 3, 16, or 17. However, Taubert et al. does not disclose a novel di-steroidal prodrug of ethinyl estradiol that is linked at the 3′C position of the ethinyl estradiol moiety.
While ethinyl estradiol has been preferred over 17β-estradiol for use in contraception, there are some disadvantages associated with the use of ethinyl estradiol. For example, not all of the ethinyl estradiol that is administered is biologically available. Ethinyl estradiol is metabolized in the intestinal wall and liver, which affects its bioavailability. Moreover, its bioavailability may vary somewhat from individual to individual (Journal of Steroid Biochemistry and Molecular Biology, 1991; 6: 733–736). In addition, it has been observed that as ethinyl estradiol is metabolized in the liver, enterohepatic recycling occurs (Methods And Findings in Experimental Clinical Pharmacology, 1982; 4: 133–42).
A novel prodrug of ethinyl estradiol, that impoves bioavailability would be highly advantageous.